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ARTICLE IN BRIEF

Pregnancy is always a challenge for neurologists taking care of woman with epilepsy. First, there is the high risk for fetal malformations associated with several antiepileptic drugs (AEDs). And there is also the worry that pregnancy-related changes in antiepileptic drug levels may put their patients at increased risk for seizures. This concern has led to routine therapeutic drug monitoring during pregnancy.

But a small pilot study presented at the AAN annual meeting in March in San Diego suggests that concentrations of carbamazepine do not change during the course of pregnancy and have no bearing on the risk for seizures.

Page Pennell, MD, associate professor of neurology at Harvard Medical School and director of epilepsy research at Brigham and Women's Hospital, and her colleagues knew that many women of childbearing age are prescribed carbamazepine as the safer alternative to other AEDs that have a higher risk for major congenital malformations. If blood levels of drugs decrease during pregnancy, how do neurologists increase the dosage to treat the mother but also spare the developing child from the effects of drug exposure?

STUDY METHOD

With a mixed scientific literature on carbamazepine level changes during pregnancy, Dr. Pennell's team set out to test women of childbearing age prior to pregnancy through to the post-partum period. Every month they would measure total and free carbamazepine levels and a metabolite (CBZ-epoxide) to see whether serum levels would change throughout pregnancy and in weeks after delivery and whether it would impact the frequency of seizures.

The assays were completed in batches in a single lab. Concentrations of total and free carbamazepine and CBZ-epoxide were obtained to compare the median apparent oral clearances [(mg/kg)/(mg/L)] for each compound, between baseline and each trimester (TM1, TM2, TM3), and between trimesters. The seizure frequency was examined for association with changes in CBZ concentrations.

They followed 13 pregnant women and tested 152 serum samples. No significant decrease occurred in the serum concentrations of total and free carbamazepine or CBZ-epoxide. To account for dose and body weight, oral clearances of each compound were calculated. The median clearances [(mg/kg)/(mg/L)] for total CBZ were 1.57 (baseline), 1.35 (TM1), 1.36 (TM2), and 1.74 (TM3); free CBZ clearances were 8.34 (baseline), 4.7(TM1), 7.67(TM2), and 5.71(TM3). Dr. Pennell said that pair-wise comparisons did not show significant change in clearance from baseline relative to any trimester. Also, total and free CBZ-epoxide clearance changes were non-significant. However, a comparison of time periods showed a significant increase in the free fraction of carbamazepine throughout pregnancy, from 0.23 at baseline to 0.32 in the third trimester (p=0.006); as well as the free fraction of CBZ-epoxide from baseline to the first trimester (0.56 to 0.71, p=0.03).

Seizure data from nine women on carbamazepine monotherapy showed that four of them had worsening seizure control during the first two months of pregnancy compared with their pre-pregnancy baseline. The increase in the seizure frequency was not associated with any change in total or free carbamazepine or CBZ-epoxide concentrations. “This is good news for women of childbearing age who want to get pregnant,” said Dr. Pennell.

“Carbamazepine may be an especially favorable option when the ability to obtain monthly AED levels is limited by available resources, either in the US or other parts of the world,” she added. “The increase in the free fraction of both compounds during pregnancy likely helps protect against any seizure worsening that has been observed with increased clearance of other AEDs.”

Harvard neurology resident Emily Johnson, MD, reported the results of the study during a poster session at the AAN meeting.

Dr. Pennell said that while the number of women in this prospective study is small, it does raise the question of the necessity of therapeutic drug monitoring for carbamazepine. Current AAN guidelines, which she helped draft, recommend the monitoring of carbamazepine levels during pregnancy. “I recognize that this is a relatively small sample size and needs to be replicated in a larger study,” before making any definitive recommendations, she added.

The neurologist is also looking at hormone changes during pregnancy to see whether she can figure out why seizure frequency does increase in around 25 percent of women during pregnancy. She noted that a number of studies are monitoring outcomes for children born to women with epilepsy. The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study followed children exposed to a number of AEDs in utero through to six years old, and found that children exposed in utero to carbamazepine did well on neuropsychological measures, Dr. Pennell said. She is now involved in a multicenter expansion of the NEAD study. In addition, the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study groups will be looking at maternal outcomes as well as neurodevelopmental effects on the children born to these mothers with epilepsy.

EXPERTS WEIGH IN

“We have thought of carbamazepine as a drug that remains stable during pregnancy, and this study confirms that,” said Cynthia Harden, MD, chief of EEG and epilepsy at North Shore-LIJ Health System in New York. “The findings suggest that clinicians and patients don't have to worry about carbamazepine levels dropping during pregnancy and triggering more seizures. It provides a level of comfort.”

“This is an important finding,” added Kimford J. Meador, MD, professor and director of epilepsy in the department of neurology at Emory University. “We don't have enough data on the effects of epilepsy drugs during pregnancy. But we know there are several antiepileptic drugs whose concentrations are significantly altered by pregnancy.”

He said that it is too early to know whether the safety profile of carbamazepine means that doctors won't have to order routine blood tests to monitor drug levels. “We need a larger study on carbamazepine clearance during pregnancy,” added Dr. Meador, the principal investigator of the NEAD Study Group.

“While historically there was alarm concerning the drop in the older AED serum concentrations during pregnancy, it has become clear that the drop is much less when the free or bioavailable — that is, non-protein bound — portions are considered,” added Andrew Herzog, MD, professor of neurology at Beth Israel Deaconess Medical Center.

Dr. Herzog runs the web-based Epilepsy Birth Control Registry. “This study supports the conclusion that there is no significant drop in clearance of CBZ during pregnancy and suggests no relationship to change in seizure frequency. The difficulty with the negative conclusions using small sample size is that no power of the comparisons is cited, that is, a larger sample size may be required to state reliably a negative conclusion and avoid a beta error.”

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